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Objective To determine whether machine learning techniques would enhance our ability to incorporate key variables into a parsimonious model with optimized prediction performance for electroencephalographic seizure (ES) prediction in critically ill children. Methods We analyzed data from a prospective observational cohort study of 719 consecutive critically ill children with encephalopathy who underwent clinically-indicated continuous EEG monitoring (CEEG). We implemented and compared three state-of-the-art machine learning methods for ES prediction: (1) random forest; (2) Least Absolute Shrinkage and Selection Operator (LASSO); and (3) Deep Learning Important FeaTures (DeepLIFT). We developed a ranking algorithm based on the relative importance of each variable derived from the machine learning methods. Results Based on our ranking algorithm, the top five variables for ES prediction were: (1) epileptiform discharges in the initial 30 minutes, (2) clinical seizures prior to CEEG initiation, (3) sex, (4) age dichotomized at 1 year, and (5) epileptic encephalopathy. Compared to the stepwise selection-based approach in logistic regression, the top variables selected by our ranking algorithm were more informative as models utilizing the top variables achieved better prediction performance evaluated by prediction accuracy, AUROC and F1 score. Adding additional variables did not improve and sometimes worsened model performance. Conclusion The ranking algorithm was helpful in deriving a parsimonious model for ES prediction with optimal performance. However, application of state-of-the-art machine learning models did not substantially improve model performance compared to prior logistic regression models. Thus, to further improve the ES prediction, we may need to collect more samples and variables that provide additional information.

Objective Electroencephalographic seizures (ESs) are common in encephalopathic critically ill children, but identification requires extensive resources for continuous electroencephalographic monitoring (CEEG). In a previous study, we developed a clinical prediction rule using three clinical variables (age, acute encephalopathy category, clinically evident seizure[s] prior to CEEG initiation) and two electroencephalographic (EEG) variables (EEG background category and interictal discharges within the first 30 minutes of EEG) to identify patients at high risk for ESs for whom CEEG might be essential. In the current study, we aimed to validate the ES prediction model using an independent cohort. Methods The prospectively acquired validation cohort consisted of 314 consecutive critically ill children treated in the Pediatric Intensive Care Unit of a quaternary care referral hospital with acute encephalopathy undergoing clinically indicated CEEG. We calculated test characteristics using the previously developed prediction model in the validation cohort. As in the generation cohort study, we selected a 0.10 cutpoint to emphasize sensitivity. Results The incidence of ESs in the validation cohort was 22%. The generation and validation cohorts were alike in most clinical and EEG characteristics. The ES prediction model was well calibrated and well discriminating in the validation cohort. The model had a sensitivity of 90%, specificity of 37%, positive predictive value of 28%, and negative predictive value of 93%. If applied, the model would limit 31% of patients from undergoing CEEG while failing to identify 10% of patients with ESs. The model had similar performance characteristics in the generation and validation cohorts. Significance A model employing five readily available clinical and EEG variables performed well when validated in a new consecutive cohort. Implementation would substantially reduce CEEG utilization, although some patients with ESs would not be identified. This model may serve a critical role in targeting limited CEEG resources to critically ill children at highest risk for ESs.

ObjectivesTo determine the optimal duration of continuous EEG monitoring (CEEG) for electrographic seizure (ES) identification in critically ill children.MethodsWe performed a prospective observational cohort study of 719 consecutive critically ill children with encephalopathy. We evaluated baseline clinical risk factors (age and prior clinically evident seizures) and emergent CEEG risk factors (epileptiform discharges and ictal-interictal continuum patterns) using a multistate survival model. For each subgroup, we determined the CEEG duration for which the risk of ES was ResultsES occurred in 184 children (26%). Patients achieved ConclusionsA model derived from 2 baseline clinical risk factors and emergent EEG risk factors would allow clinicians to implement personalized strategies that optimally target limited CEEG resources. This would enable more widespread use of CEEG-guided management as a potential neuroprotective strategy.ClinicalTrials.gov identifierNCT03419260.

OBJECTIVE Electroencephalographic seizures (ESs) are common in encephalopathic critically ill children, but ES identification with continuous electroencephalography (EEG) monitoring (CEEG) is resource-intense. We aimed to develop an ES prediction model that would enable clinicians to stratify patients by ES risk and optimally target limited CEEG resources. We aimed to determine whether incorporating data from a screening EEG yielded better performance characteristics than models using clinical variables alone. METHODS We performed a prospective observational study of 719 consecutive critically ill children with acute encephalopathy undergoing CEEG in the pediatric intensive care unit of a quaternary care institution between April 2017 and February 2019. We identified clinical and EEG risk factors for ES. We evaluated model performance with area under the receiver-operating characteristic (ROC) curve (AUC), validated the optimal model with the highest AUC using a fivefold cross-validation, and calculated test characteristics emphasizing high sensitivity. We applied the optimal operating slope strategy to identify the optimal cutoff to define whether a patient should undergo CEEG. RESULTS The incidence of ES was 26%. Variables associated with increased ES risk included age, acute encephalopathy category, clinical seizures prior to CEEG initiation, EEG background, and epileptiform discharges. Combining clinical and EEG variables yielded better model performance (AUC 0.80) than clinical variables alone (AUC 0.69; P

We aimed to determine the incidence of periodic and rhythmic patterns (PRP), assess the interrater agreement between electroencephalographers scoring PRP using standardized terminology, and analyze associations between PRP and electrographic seizures (ES) in critically ill children.This was a prospective observational study of consecutive critically ill children undergoing continuous electroencephalographic monitoring (CEEG). PRP were identified by one electroencephalographer, and then two pediatric electroencephalographers independently scored the first 1-h epoch that contained PRP using standardized terminology. We determined the incidence of PRPs, evaluated interrater agreement between electroencephalographers scoring PRP, and evaluated associations between PRP and ES.One thousand three hundred ninety-nine patients underwent CEEG. ES occurred in 345 (25%) subjects. PRP, ES + PRP, and ictal-interictal continuum (IIC) patterns occurred in 142 (10%), 81 (6%), and 93 (7%) subjects, respectively. The most common PRP were generalized periodic discharges (GPD; 43, 30%), lateralized periodic discharges (LPD; 34, 24%), generalized rhythmic delta activity (GRDA; 34, 24%), bilateral independent periodic discharges (BIPD; 14, 10%), and lateralized rhythmic delta activity (LRDA; 11, 8%). ES risk varied by PRP type (p .01). ES occurrence was associated with GPD (odds ratio [OR] = 6.35, p .01), LPD (OR = 10.45, p .01), BIPD (OR = 6.77, p .01), and LRDA (OR = 6.58, p .01). Some modifying features increased the risk of ES for each of those PRP. GRDA was not significantly associated with ES (OR = 1.34, p = .44). Each of the IIC patterns was associated with ES (OR = 6.83-8.81, p .01). ES and PRP occurred within 6 h (before or after) in 45 (56%) subjects.PRP occurred in 10% of critically ill children who underwent CEEG. The most common patterns were GPD, LPD, GRDA, BIPD, and LRDA. The GPD, LPD, BIPD, LRDA, and IIC patterns were associated with ES. GRDA was not associated with ES.

ObjectiveTo determine the association between electroencephalographic seizure (ES) and electroencephalographic status epilepticus (ESE) exposure and unfavorable neurobehavioral outcomes in critically ill children with acute encephalopathy.MethodsThis was a prospective cohort study of acutely encephalopathic critically ill children undergoing continuous EEG monitoring (CEEG). ES exposure was assessed as (1) no ES/ESE, (2) ES, or (3) ESE. Outcomes assessed at discharge included the Glasgow Outcome Scale–Extended Pediatric Version (GOS-E-Peds), Pediatric Cerebral Performance Category (PCPC), and mortality. Unfavorable outcome was defined as a reduction in GOS-E-Peds or PCPC score from preadmission to discharge. Stepwise selection was used to generate multivariate logistic regression models that assessed associations between ES exposure and outcomes while adjusting for multiple other variables.ResultsAmong 719 consecutive critically ill patients, there was no evidence of ES in 535 patients (74.4%), ES occurred in 140 patients (19.5%), and ESE in 44 patients (6.1%). The final multivariable logistic regression analyses included ES exposure, age dichotomized at 1 year, acute encephalopathy category, initial EEG background category, comatose at CEEG initiation, and Pediatric Index of Mortality 2 score. There was an association between ESE and unfavorable GOS-E-Peds (odds ratio 2.21, 95% confidence interval 1.07–4.54) and PCPC (odds ratio 2.17, 95% confidence interval 1.05–4.51) but not mortality. There was no association between ES and unfavorable outcome or mortality.ConclusionsAmong acutely encephalopathic critically ill children, there was an association between ESE and unfavorable neurobehavioral outcomes, but no association between ESE and mortality. ES exposure was not associated with unfavorable neurobehavioral outcomes or mortality.

Rationale Implementation of electronic health records may improve the quality, accuracy, timeliness, and availability of documentation. Thus, our institution developed a system that integrated EEG ordering, scheduling, standardized reporting, and billing. Given the importance of user perceptions for successful implementation, we performed a quality improvement study to evaluate electroencephalographer satisfaction with the new EEG report system. Methods We implemented an EEG report system that was integrated in an electronic health record. In this single-center quality improvement study, we surveyed electroencephalographers regarding overall acceptability, report standardization, workflow efficiency, documentation quality, and fellow education using a 0 to 5 scale (with 5 denoting best). Results Eighteen electroencephalographers responded to the survey. The median score for recommending the overall system to a colleague was 5 (range 3-5), which indicated good overall satisfaction and acceptance of the system. The median scores for report standardization (4; 3-5) and workflow efficiency (4.5; 3-5) indicated that respondents perceived the system as useful and easy to use for documentation tasks. The median scores for quality of documentation (4.5; 1-5) and fellow education (4; 1-5) indicated that although most respondents believed the system provided good quality reports and helped with fellow education, a small number of respondents had substantially different views (ratings of 1). Conclusions Overall electroencephalographer satisfaction with the new EEG report system was high, as were the scores for perceived usefulness (assessed as standardization, documentation quality, and education) and ease of use (assessed as workflow efficiency). Future study is needed to determine whether implementation yields useful data for clinical research and quality improvement studies or improves EEG report standardization.

This article examined response format effects on norm prevalence (i.e., the percent of individuals who could specify a norm). Data were collected in Dilek Peninsula Büyük Menderes Delta National Park, in Turkey. Respondents were randomly assigned to one of two conditions. In the “semi-open” response format, respondents (n = 458) “wrote a number” for an acceptable number of visitor encounters. In the “closed” format, respondents (n = 459) “circled a number” of acceptable encounters, along a range of possible responses. Results showed that encounter norm prevalence was significantly and consistently higher for the closed format of the survey, as compared to the semi-open version. In addition, among those reporting a norm, the average tolerance levels were statistically higher in the semi-open format. Implications for applying the normative approach across different cultures are discussed.

Objective Guidelines recommend that encephalopathic critically ill children undergo continuous electroencephalographic (CEEG) monitoring for electrographic seizure (ES) identification and management. However, limited data exist on antiseizure medication (ASM) safety for ES treatment in critically ill children. Methods We performed a single-center prospective observational study of encephalopathic critically ill children undergoing CEEG. Clinical and EEG features and ASM utilization patterns were evaluated. We determined the incidence, types, and risk factors for adverse events associated with ASM administration. Results A total of 472 consecutive critically ill children undergoing CEEG were enrolled. ES occurred in 131 children (28%). Clinicians administered ASM to 108 children with ES (82%). ES terminated after the initial ASM in 38% of patients who received one ASM, after the second ASM in 35% of patients who received two ASMs, after the third ASM in 50% of patients who received three ASMs, and after the fourth ASM in 53% of patients who received four ASMs. Thirty patients (28%) received anesthetic infusions for ES management. Adverse events occurred in 18 patients (17%). Adverse effects were expected and resolved in all patients, and they were generally serious (in 15 patients) and definitely related (in 12 patients). Adverse events were rare in patients with acute symptomatic seizures requiring only one to two ASMs for treatment, but were more common in children with epilepsy, ictal-interictal continuum EEG patterns, or patients requiring more extensive ASM management. Significance ES ceased after one ASM in only 38% of critically ill children but ceased after two ASMs in 73% of critically ill children. Thus, ES management was often accomplished with readily available medications, but optimization of multistep ES management strategies might be beneficial. Adverse events were rare and manageable in children with acute symptomatic seizures requiring only one to two ASMs for treatment. Future studies are needed to determine whether management of acute symptomatic ES improves neurobehavioral outcomes.

Objective To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS). Methods We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy >18 months, 6 on interferon β-1a monotherapy >36 months, and 5 untreated controls. We performed quantitative real-time polymerase chain reaction in cerebrospinal fluid (CSF), blood, and urine for JCV DNA, and we determined JCV-specific T-cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides. Results JCV DNA was detected in the CSF of 2 of 27 (7.4%) natalizumab-treated MS patients who had no symptoms or magnetic resonance imaging–detected lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12 of 43 (27.9%) and in urine of 11 of 43 (25.6%) subjects without a difference between natalizumab-treated patients and controls. JC viral load was higher in CD34+ cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot. JCV-specific T-cell responses, mediated by both CD4+ and CD8+ T lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4+ T cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34+ (p = 0.05) and B cells (p = 0.03). Interpretation Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34+ cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4+ T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment. ANN NEUROL 2014;75:925–934

Summary Objectives We aimed to determine whether implementation of a structured multidisciplinary electroencephalography (EEG) monitoring pathway improved the timeliness of administration of antiseizure medication in response to electrographic seizures in encephalopathic critically ill children. Methods A multidisciplinary team developed a pathway to standardize EEG monitoring and seizure management in encephalopathic critically ill children, aiming to decrease the time from electrographic seizure onset to antiseizure medication administration. Data were collected to inform the team of improvement opportunities, which were then provided by an institutional pathway, staff education, and streamlined communication. Measurements were obtained before and after pathway implementation to assess for improvement. Results We collected data on 41 patients before and 21 after pathway implementation. There were no differences between the baseline and pathway groups in demographic characteristics, acute encephalopathy etiologies, or antiseizure medications utilized. The median duration [interquartile range, IQR] from seizure onset to antiseizure medication administration was shorter for patients treated with the pathway (64 min [50, 101]) compared to patients treated prior to pathway implementation (139 min [71, 189]; p = 0.0006). The median [IQR] interval from seizure onset to antiseizure medication order was shorter for the pathway group (31 min [20, 49]) than the baseline group (71 min [33, 131]; p = 0.003). The median [IQR] interval from antiseizure medication order to administration was shorter for the pathway group (30 min [19, 40]) than the baseline group (40 min [17, 68]) (p = 0.047). Seizure termination was more likely to occur following initial antiseizure medication administration in the pathway than baseline group (67% vs. 27%, p = 0.002). Significance Implementation of the pathway resulted in a significant reduction in the duration between electrographic seizure onset and antiseizure medication administration, and a significant increase in the rate of electrographic seizure termination following an initial antiseizure medication. Further study is needed to determine whether these changes are associated with improved outcomes.

Therapeutic hypothermia is being utilized as a neuro-protective strategy in neonates, children, and adults. The most common indications are hypoxic ischemic encephalopathy in neonates and post cardiac arrest in adults. Electroencephalographic monitoring use is increasing in critical care units, and is sometimes a component of therapeutic hypothermia clinical pathways. Monitoring may detect non-convulsive seizures or non-convulsive status epilepticus, and it may provide prognostic information. We review data regarding indications for therapeutic hypothermia and electroencephalographic monitoring in neonatal, pediatric, and adult critical care units, and discuss technical aspects related to such monitoring.

Background: Retrospective studies have reported the occurrence of nonconvulsive seizures in critically ill children. We aimed to prospectively determine the incidence and risk factors of nonconvulsive seizures in critically ill children using predetermined EEG monitoring indications and EEG interpretation terminology. Methods: Critically ill children (non-neonates) with acute encephalopathy underwent continuous EEG monitoring if they met institutional clinical practice criteria. Study enrollment and data collection were prospective. Logistic regression analysis was utilized to identify risk factors for seizure occurrence. Results: One hundred children were evaluated. Electrographic seizures occurred in 46 and electrographic status epilepticus occurred in 19. Seizures were exclusively nonconvulsive in 32. The only clinical risk factor for seizure occurrence was younger age ( p = 0.03). Of patients with seizures, only 52% had seizures detected in the first hour of monitoring, while 87% were detected within 24 hours. Conclusions: Seizures were common in critically ill children with acute encephalopathy. Most were nonconvulsive. Clinical features had little predictive value for seizure occurrence. Further study is needed to confirm these data in independent high-risk populations, to clarify which children are at highest risk for seizures so limited monitoring resources can be allocated optimally, and to determine whether seizure detection and management improves outcome.

Mereological principles are sometimes used to support general claims about the structure and arrangement of objects in the world. I focus initially on one such mereological principle, the weak supplementation principle (WSP). It is not obvious that (WSP) is prescribed by ordinary thinking about parthood. Further, (WSP) is not needed for a fairly strong formal characterization of the part–whole relation. For these reasons, some arguments relying on (WSP) might be countered by simply denying (WSP). I argue more generally that there is no reason to assume that one core mereology functions as a common basis for all plausible metaphysical theories.

Electroencephalographic (EEG) features may provide objective data regarding prognosis in children resuscitated from cardiac arrest (CA), but therapeutic hypothermia (TH) may impact its predictive value. We aimed to determine whether specific EEG features were predictive of short-term outcome in children treated with TH after CA, both during hypothermia and after return to normothermia.Thirty-five children managed with a standard clinical TH algorithm after CA were prospectively enrolled. EEG recordings were scored in a standardized manner and categorized. EEG category 1 consisted of continuous and reactive tracings. EEG category 2 consisted of continuous but unreactive tracings. EEG category 3 included those with any degree of discontinuity, burst suppression, or lack of cerebral activity. The primary outcome was unfavorable short-term outcome defined as Pediatric Cerebral Performance Category score of 4-6 (severe disability, vegetative, death) at hospital discharge. Univariate analyses of the association between EEG category and outcome was performed using logistic regression.For tracings obtained during hypothermia, patients with EEGs in categories 2 or 3 were far more likely to have poor outcome than those in category 1 (OR 10.7, P = 0.023 and OR 35, P = 0.004, respectively). Similarly, for tracings obtained during normothermia, patients with EEGs in categories 2 or 3 were far more likely to have poor outcomes than those in category 1 (OR 27, P = 0.006 and OR 18, P = 0.02, respectively).A simple EEG classification scheme has predictive value for short-term outcome in children undergoing TH after CA.

Continuous EEG (cEEG) monitoring is being used with increasing frequency in critically ill patients, most often to detect non-convulsive seizures. While cEEG is non-invasive and feasible in the critical care setting, it is also expensive and labor intensive, and there has been little study of its impact on clinical care. We aimed to determine prospectively the impact of cEEG on clinical management in critically ill children.Critically ill children (non-neonates) with acute encephalopathy underwent cEEG. Study enrollment and data collection were prospective.100 children were studied. EEG monitoring led to specific clinical management changes in 59 children. These included initiating or escalating anti-seizure medications in 43 due to seizure detection, demonstrating that a specific event (subtle movement or vital sign change) was not a seizure in 21, or obtaining urgent neuroimaging that led to a clinical change in 3. In the remaining 41 children, cEEG ruled out the presence of non-convulsive seizures but did not lead to a specific change in clinical management.EEG monitoring led to changes in clinical management in the majority of patients, suggesting it may have an important role in management of critically ill children. Further study is needed to determine whether the management changes elicited by cEEG improve outcome.

In this paper, I focus on three issues intertwined in current debates between endurantists and perdurantists—(i) the dimension of persisting objects, (ii) whether persisting objects have timeless, or only time-relative, parts, and (iii) whether persisting objects have proper temporal parts. I argue that one standard endurantist position on the first issue is compatible with standard perdurantist positions on parthood and temporal parts. I further argue that different accounts of persistence depend on the claims about objects’ dimensions and not on the auxiliary claims about parthood and temporal parts.

This paper presents an axiomatic formalization of a theory of top-level relations between three categories of entities: individuals, universals, and collections. We deal with a variety of relations between entities in these categories, including the sub-universal relation among universals and the parthood relation among individuals, as well as cross-categorial relations such as instantiation and membership. We show that an adequate understanding of the formal properties of such relations-in particular their behavior with respect to time-is critical for geographic information processing. The axiomatic theory is developed using Isabelle, a computational system for implementing logical formalisms. All proofs are computer verified and the computational representation of the theory is available online.

Background: Hypoxic ischemic brain injury secondary to pediatric cardiac arrest (CA) may result in acute symptomatic seizures. A high proportion of seizures may be nonconvulsive, so accurate diagnosis requires continuous EEG monitoring. We aimed to determine the safety and feasibility of long-term EEG monitoring, to describe electroencephalographic background and seizure characteristics, and to identify background features predictive of seizures in children undergoing therapeutic hypothermia (TH) after CA. Methods: Nineteen children underwent TH after CA. Continuous EEG monitoring was performed during hypothermia (24 hours), rewarming (12–24 hours), and then an additional 24 hours of normothermia. The tolerability of these prolonged studies and the EEG background classification and seizure characteristics were described in a standardized manner. Results: No complications of EEG monitoring were reported or observed. Electrographic seizures occurred in 47% (9/19), and 32% (6/19) developed status epilepticus. Seizures were nonconvulsive in 67% (6/9) and electrographically generalized in 78% (7/9). Seizures commenced during the late hypothermic or rewarming periods (8/9). Factors predictive of electrographic seizures were burst suppression or excessively discontinuous EEG background patterns, interictal epileptiform discharges, or an absence of the expected pharmacologically induced beta activity. Background features evolved over time. Patients with slowing and attenuation tended to improve, whereas those with burst suppression tended to worsen. Conclusions: EEG monitoring in children undergoing therapeutic hypothermia after cardiac arrest is safe and feasible. Electrographic seizures and status epilepticus are common in this setting but are often not detectable by clinical observation alone. The EEG background often evolves over time, with milder abnormalities improving and more severe abnormalities worsening. BS = burst suppression; CA = cardiac arrest; CPR = cardiopulmonary resuscitation; DD = developmental delay; FEN = fentanyl; FOS = fosphenytoin; HIE = hypoxic ischemic encephalopathy; LEV = levetiracetam; LZP = lorazepam; MDZ = midazolam; NCS = nonconvulsive seizures; NCSE = nonconvulsive status epilepticus; NPV = negative predictive value; PB = phenobarbital; PED = periodic epileptiform discharge; PICU = pediatric intensive care unit; PPV = positive predictive value; SE = status epilepticus; SIDS = sudden infant death syndrome; sz = seizures; TH = therapeutic hypothermia; VEC = vecuronium; VPA = valproic acid; VT = ventricular tachycardia.

It is often assumed that indeterminacy in mereological relations—in particular, indeterminacy in which collections of objects have fusions—leads immediately to indeterminacy in what objects there are in the world. This assumption is generally taken as a reason for rejecting mereological vagueness. The purpose of this paper is to examine the link between mereological vagueness and existential vagueness. I hope to show that the connection between the two forms of vagueness is not nearly so clear-cut as has been supposed.

According to the prevalent 'sum view' of stuffs, each portion of stuff is a mereological sum of its subportions. The purpose of this paper is to re-examine the sum view in the light of a modal temporal mereology which distinguishes between different varieties of summation relations. While admitting David Barnett's recent counter-example to the sum view (Barnett, Philos Rev 113:89-100, 2004), we show that there is nonetheless an important sense in which all portions of stuff are sums of their subportions. We use our summation relations to develop, as an alternative to the sum view, an analysis of stuffs that distinguishes between the ways in which different sorts of stuffs are sums of their subportions.

Objective: The objective of this paper is to demonstrate how a formal spatial theory can be used as an important tool for disambiguating the spatial information embodied in biomedical ontologies and for enhancing their automatic reasoning capabilities. Method and materials: This paper presents a formal theory of parthood and location relations among individuals, called Basic Inclusion Theory (BIT). Since biomedical ontologies are comprised of assertions about classes of individuals (rather than assertions about individuals), we define parthood and location relations among classes in the extended theory Basic Inclusion Theory for Classes (BIT+Cl). We then demonstrate the usefulness of this formal theory for making the logical structure of spatial information more precise in two ontologies concerned with human anatomy: the Foundational Model of Anatomy (FMA) and GALEN. Results: We find that in both the FMA and GALEN, class-level spatial relations with different logical properties are not always explicitly distinguished. As a result, the spatial information included in these biomedical ontologies is often ambiguous and the possibilities for implementing consistent automatic reasoning within or across ontologies are limited. Conclusion: Precise formal characterizations of all spatial relations assumed by a biomedical ontology are necessary to ensure that the information embodied in the ontology can be fully and coherently utilized in a computational environment. This paper can be seen as an important beginning step toward achieving this goal, but much more work along these lines is required.

In fields such as medicine, geography, and mechanics, spatial reasoning involves reasoning about entities that may coincide without overlapping. Some examples are: cavities and invading particles, passageways and valves, geographic regions and tropical storms. The purpose of this paper is to develop a formal theory of spatial relations for domains that include coincident entities. The core of the theory is a clear distinction between mereotopological relations, such as parthood and connection, and relative location relations, such as coincidence. To guide the development of the formal theory, I construct mathematical models in which nontrivial relative location relations are defined.

There is a significant lack of scientific data to support the clinically accepted view that 25 to 30 mm Hg is the maximum safe perfusion pressure during retrograde cerebral perfusion (RCP). This study was designed to investigate whether perfusion pressure greater than 30 mm Hg during RCP is beneficial to the brain during prolonged HCA in an acute porcine model.Sixteen pigs underwent 120 minutes of circulatory arrest in conjunction with RCP at a perfusion pressure of either 23 to 29 mm Hg (group L, n = 8) or 34 to 40 mm Hg (group H, n = 8) at 15 degrees C, followed by 60 minutes of normothermic cardiopulmonary bypass. Cortical blood flow and oxygenation were measured continuously with a laser flowmeter and near-infrared spectroscopy, respectively. Tissue water content was measured at the end of the experiments.Brain tissue blood flow was significantly higher in group H than in group L (16.8% +/- 4.1% vs 4.8% +/- 0.9% of baseline, p0.01) during RCP. Brain oxygen extraction in group L reached a maximum (approximately 70%) immediately after starting RCP, whereas in group H it increased gradually and reached a maximum at 120 minutes of RCP, indicating a greater supply of oxygen to tissue in group H than in group L. After RCP, the ability of brain tissue to use oxygen was better preserved in group H than in group L, as indicated by tissue oxygen saturation and the deoxyhemoglobin level. There was no significant increase in tissue water content in either group (group H 79.2% +/- 0.3%, group L 79.1% +/- 0.4%) relative to normal control pigs (78.7% +/- 0.1%).In this acute porcine model, increasing perfusion pressure from 23-29 to 34-40 mm Hg during RCP increases tissue blood flow and provides better tissue oxygenation, without increasing tissue edema. The optimal perfusion pressure for RCP needs to be further investigated.

To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS).We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy18 months, 6 on interferon β-1a monotherapy36 months, and 5 untreated controls. We performed quantitative real-time polymerase chain reaction in cerebrospinal fluid (CSF), blood, and urine for JCV DNA, and we determined JCV-specific T-cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides.JCV DNA was detected in the CSF of 2 of 27 (7.4%) natalizumab-treated MS patients who had no symptoms or magnetic resonance imaging-detected lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12 of 43 (27.9%) and in urine of 11 of 43 (25.6%) subjects without a difference between natalizumab-treated patients and controls. JC viral load was higher in CD34(+) cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot. JCV-specific T-cell responses, mediated by both CD4(+) and CD8(+) T lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4(+) T cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34(+) (p = 0.05) and B cells (p = 0.03).Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34(+) cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4(+) T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment.

Therapeutic hypothermia is being utilized as a neuro-protective strategy in neonates, children, and adults. The most common indications are hypoxic ischemic encephalopathy in neonates and post cardiac arrest in adults. Electroencephalographic monitoring use is increasing in critical care units, and is sometimes a component of therapeutic hypothermia clinical pathways. Monitoring may detect non-convulsive seizures or non-convulsive status epilepticus, and it may provide prognostic information. We review data regarding indications for therapeutic hypothermia and electroencephalographic monitoring in neonatal, pediatric, and adult critical care units, and discuss technical aspects related to such monitoring.

Electrographic seizures are common in neonates with hypoxic-ischemic encephalopathy, but detailed data are not available regarding seizure incidence during therapeutic hypothermia. The objective of this prospective study was to determine the incidence and timing of electrographic seizures in term neonates undergoing whole-body therapeutic hypothermia for hypoxic-ischemic encephalopathy as detected by conventional full-array electroencephalography for 72 hours of therapeutic hypothermia and 24 hours of normothermia. Clinical and electroencephalography data were collected from 26 consecutive neonates. Electroencephalograms were reviewed by 2 pediatric neurophysiologists. Electrographic seizures occurred in 17 of 26 (65%) patients. Seizures were entirely nonconvulsive in 8 of 17 (47%), status epilepticus occurred in 4 of 17 (23%), and seizure onset was in the first 48 hours in 13 of 17 (76%) patients. Electrographic seizures were common, were often nonconvulsive, and had onset over a broad range of times in the first days of life.

Poison frogs contain an alkaloid-based chemical defense that is sequestered directly from a diet of alkaloid-containing arthropods. Geographic and temporal variation in alkaloid defense is common in poison frogs and is generally attributed to differences in the availability of alkaloid-containing arthropods. Variable chemical defense in poison frogs may have important consequences for predator-prey interactions, requiring a full understanding of the factors involved in explaining such variation. In the present study, we examine alkaloid variation in the dendrobatid poison frog Oophaga pumilio between males and females on Cayo Nancy (Isla Solarte), located in the Bocas del Toro archipelago of Panama. On average, females contained a significantly larger number and quantity of alkaloids when compared to males. Alkaloid composition varied significantly between males and females, illustrating that chemical defense in this population of O. pumilio is sex-dependent. The variation in alkaloids between sexes is attributed to differences in feeding and behavior between males and females. The majority of alkaloids present in the skin of O. pumilio appear to be of oribatid mite origin, supporting the importance of these dietary arthropods in the chemical defense of poison frogs.

Standard theories in mereotopology focus on relations of parthood and connection among spatial or spatio-temporal regions. Objects or processes which might be located in such regions are not normally directly treated in such theories. At best, they are simulated via appeal to distributions of attributes across the regions occupied or by functions from times to regions. The present paper offers a richer framework, in which it is possible to represent directly the relations between entities of various types at different levels, including both objects and the regions they occupy. What results is a layered mereotopology, a theory which can handle multiple layers (analogous to the layers of a lasagna) of spatially or spatiotemporally coincident but mereologically non-overlapping entities.

No studies testing the safety of changing intravenous systems containing in-line burettes at 72 hours in an intensive care setting have been performed. Patients entering a medical or surgical intensive care unit were alternatively assigned to have any line with an in-line burette changed at either 48 hour (105 patients) or 72 hour (65 patients) intervals. Daily quantitative cultures with a 2 ml aliquot of burette fluid were obtained. Contaminated burette fluid was detected in 60 of 1181 (5.0%, 95% confidence interval, 3.7% to 6.3%) samples from the burettes changed at 48 hour intervals, and in 40 of 901 (4.4%, 95% confidence interval, 3.0% to 5.8%) samples from 72 hour interval burettes. Significant bacterial contamination of burette fluid, defined as ten or more colonies per milliliter, occurred in only seven (0.6%) cultures from patients in the 48 hour interval group compared with only three (0.3%) cultures in the 72 hour group. None of the contaminated burette fluids was associated with a primary bacteremia. Change of inline burettes in patients in intensive care at 72-hour intervals is safe and should result in substantial cost savings to hospitals.